C O M M U N I C A T I O N S
Scheme 5 a
a
i
a) i. 26, Pr2NEt, CH2Cl2, -78 °C; ii. 3. b) TBSCl, imidazole. c) i. DDQ, CH2Cl2/pH 7 buffer; ii. TMSOTf, 2,6-di-tbutylpyridine; iii. pH 5 buffer. d) 2,4,6-
Cl3C6H2COCl, Pr2NEt, 4-pyrrolidinopyridine. e) H2, Pd-CaCO3. f) i. CH2I2, Zn, PbCl2, TiCl4; ii. HF‚pyr. g) 20 mol% Ti(OiPr)4, 20 mol% (+)-DIPT, BuOOH.
i
t
R-alkoxy aldehyde 15 (Scheme 3). The synthesis began with
â-lactone 16 (92% ee) derived from the corresponding AAC
reaction. Amine-mediated ring opening and hydroxyl group protec-
tion delivered Weinreb amide 17. Following amide-to-aldehyde
interconversion, Wittig olefination, ester reduction, and alcohol
protection afforded the orthogonally protected triol 18. Silyl ether
deprotection and alcohol oxidation completed the targeted R-alkoxy
aldehyde synthon 15.
Completing the upper synthon was predicated on achieving the
diastereoselective coupling of vinyl anion 19 and R-alkoxy aldehyde
electrophile 15 (Scheme 4). The synthesis of the requisite precursor
to 19 commenced with Brown allylation12 of â-tributylstannyl
acrolein using allyl borane 20 to provide the desired secondary
alcohol (98% ee); subsequent alcohol etherification provided triene
21. Olefin metathesis within 21 was expected to exhibit a kinetic
preference for engaging the mono- and 1,1-disubstituted olefins in
six-membered ring formation in preference to the sterically more
encumbered 1,2-disubstituted stannyl alkene.13 Schrock’s Mo(VI)-
based metathesis catalyst proved especially efficient in mediating
the desired pyran ring formation to give pyran 22;14 subjecting 22
to tin-halogen exchange completed the vinyl anion precursor 23.
Coupling of 15 and 23 was achieved with complete chelate-
controlled diastereoselection by reacting the vinyl Grignard reagent
1915 derived from 23 with aldehyde 15 in dichloromethane solvent
to afford the desired C19-C20 syn-diol relationship present in 24.16
A routine protection-deprotection-oxidation sequence then com-
pleted the upper synthon 3.
new reaction methodology derived from asymmetric AAC reactions
and ensuing transformations of the derived enantioenriched â-lac-
tones.
Acknowledgment. The American Cancer Society (RPG CDD-
99301), the Bristol-Myers Squibb Foundation, and the Merck
Research Laboratories are gratefully acknowledged.
Supporting Information Available: Experimental procedures and
representative 1H and 13C spectra (PDF). This material is available free
References
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26.17,18 Reacting boron enolate 25 with the top-half aldehyde 3
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Subjecting propargylic acid 28 to modified Yamaguchi macrolac-
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29.20 Catalyzed alkyne dihydrogenation under Lindlar conditions
successfully transformed propargylic ester 29 to the requisite C2-
C3 Z-alkene 30. Paterson had previously transformed 30 to synthetic
(-)-laulimalide;3b this same sequence of C13 ketone methylenation,
silyl ether deprotection, and diastereoselective Sharpless epoxida-
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A de novo enantioselective total synthesis of (-)-laulimalide has
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